Tacrine, development

Serious hepatotoxicity of tacrine has been documented. More recent data suggest, however, that this toxicity can be reduced by carehiUy monitoring semm alanine aminotransferase levels (125). The side effects of tacrine also include gastrointestinal disturbances and emesis, and alternative AChE therapies are being advanced. Velnacrine (20), a metaboUte of tacrine, was expected to have reduced hepatotoxicity. However, its limited efficacy and side-effect profile, which includes dmg-related hematological changes, caused it to be dropped from further development. 

The limited effectiveness of physostigmine did, however, encourage the development of longer-acting orally effective anticholinesterases such as tacrine (tetrahydroamino-acrydine), velnacrine and donepezil. 

The initial enthusiasm for tacrine and velnacrine, which are the anticholinesterases most studied clinically, has been tempered by the fact that not all patients respond. Most show the peripheral parasympathomimetic effects of cholinesterase inhibition, e.g. dyspepsia and diarrhoea, as well as nausea and vomiting, and about half of the patients develop hepatotoxicity with elevated levels of plasma alanine transaminase. While some peripheral effects can be attenuated with antimuscarinics that do not enter the brain, these add further side-effects and the drop-out rate from such trials is high (<75%) in most long-term studies. Donepezil appears to show less hepatotoxicity but its long-term value remains to be determined. 

His present interests include the development of new synthetic methodologies in carbohydrates, free radical chemistry, organometallic chemistry (Pauson-Khand reaction, transition metal (PtCl2, AuCl)-mediated cycloisomerization of polyunsaturated precursors), and synthesis/biologi-cal evaluation of heterocyclic systems (CSIC reaction, tacrine analogs). 

Tacrine is not without its problems. It produces typical cholinergic side effects (nansea, cramping, loss of appetite, rnnny nose, and diarrhea). In addition, tacrine can be toxic to the liver in some patients. If liver problems develop while taking tacrine, they reverse when the medication is discontinued. Nevertheless, all patients shonld routinely undergo blood tests of liver function before starting tacrine and periodically dnring tacrine therapy. 

Rutaecarpine (46) is the major alkaloid found in Evodia rutaecarpa (Juss.) Benth., and activities relevant to AD have been identified with the extract and with rutaecarpine. Dehydroevodiamine (47), another alkaloid from the same species, inhibited AChE in vitro, and reversed scopolamine-induced memory impairment in rats and increased cerebral blood flow in vivo in cats, a property which would supplement its usefulness in AD. The structures of (46) and (47) and tacrine (28) have been used as templates for the development of a series of synthetic compounds which have been evaluated for their antiChE activity. These were found to be inhibitory against both AChE and BuChE with A -(2-phenylethyl)-A -[(12Z)-7,8,9,10-tetrahydroazepino [2,l- ]quinazolin-12(6//)-ylidene] amine (48) showing higher affinity for BuChE. 

Hypersensitivity to tacrine or acridine derivatives patients previously treated with tacrine who developed treatment-associated jaundice a serum bilirubin greater than 3 mg/dL signs or symptoms of hypersensitivity (eg, rash or fever) in association with ALT elevations. 

Gl disease/dysfunction Tacrine is an inhibitor of cholinesterase and may be expected to increase gastric acid secretion caused by increased cholinergic activity. Therefore, closely monitor patients at increased risk for developing ulcers for symptoms of active or occult Gl bleeding. 

Several inhibitors of AChE have been developed for use in treating Alzheimer s disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors. 

Contraindications Known hypersensitivity to tacrine, patients previously treated with tacrine who developed jaundice... 

One way of improving the therapeutic value of physostigmine in the treatment of AD is the use of slow-release forms. Some of these are currently in clinical development. The search for cholinesterase inhibitors with longer half-lives and stronger effects led to the discovery of the aminoacridines, tacrine and its major metabolite, velnacrine maleate [Davis and Powchik... 

FIGURE 12-30. Alzheimer s disease pharmacy. Currently, donepezil is first-line for memory loss, and atypical antipsychotics (SDA) are first-line for positive psychotic symptoms together they may work synergistically. Soon the cholinesterase inhibitors metrifonate and/or rivastigmine may become available. Second-line treatments are tacrine for memory and conventional antipsychotics (D2) for positive psychotic symptoms. Several other agents are in clinical and preclinical development. 

Tacrine is a non-competitive, irreversible inhibitor of both acetyl and butyryl cholinesterase, with a greater potency for the latter enzyme. Based on the outcome of placebo-controlled, double-blind studies, tacrine was the first anticholinesterase to be licensed for the symptomatic treatment of AD in the United States. The main disadvantage of tacrine lies in its hepatotoxicity (approximately 50% of patients were found to develop elevated liver transaminases which reversed on discontinuation of the drug). Because of such side effects and limited efficacy, tacrine is no longer widely prescribed. 

Co-culture with direct cell-to-cell contact. In a very elegant study published in 1988 by Sargent and collaborators, the lab of Max Burger has provided strong evidence that, not only paracrine growth stimulation can be critical for the development of site-specific metastasis (Burger and Madnick, 1983), but also that paracrine growth interactions may require direct cell-to-cell contact (jux-tacrine interactions). 

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